The overall goal of these studies is to elucidate the roles of different musculoskeletal factors in the loss of muscle quality with aging, with specific focus on the extracellular matrix (ECM). Sarcopenia, defined as age- associated loss of skeletal muscle mass, currently affects 50 million in the US with the number expected to rise to 200 million by 2050. The concomitant, disproportionately larger loss of muscle strength compared to size, termed dynopenia, cannot be accounted for completely by the widely believed primary causes, of neural and muscle contractility origin. Recent evidence from animal studies suggest that the ECM may be an important cause of loss of muscle quality since the more than 80% of force transmission occurring laterally through the ECM in young mice is significantly reduced in aging animals. The ECM remodels considerably with aging, in content, regional distribution, collagenous composition and cross-linking. However, the contribution of changes in the ECM to the loss of muscle quality in humans has never been investigated comprehensively. We hy- pothesize that altered lateral force transmission due to ECM remodeling contributes to dynopenia. A highly integrated array of MR imaging, neural activation, and biochemical and immuno-histochemical analysis on muscle biopsy samples, will be used to characterize the human plantar and dorsiflexor muscles in a cross-sectional study (N=30 each) of: (i) young (21-30 years) adults, (ii) active seniors (> 75 years) with min- imal dynopenia, and (iii) frail seniors (> 75 years) with significant dynopenia. To test the Hypothesis that dy- nopenia cannot be totally accounted for by decreases in muscle contractile quality, mass and neural drive, Specific Aim (SA)-1 will estimate the contributions of muscle and nerve to dynopenia by assessing age and frailty induced changes in (1) muscle mass, architecture using diffusion tensor MRI, material properties from dynamic MRI; (2) contractile quality based on ryanodine receptor modification, (3) fiber size using immu- nochemistry, and (4) muscle activation. To test the Hypothesis that ECM remodeling will account for the dis- crepancy identified in the SA-1, the contribution of ECM remodeling will be determined in SA-2 via quantifica- tion of (1) indices related to lateral transmission of force (shear strain, angle between the axis of shortening and muscle fiber from dynamic MRI), and (2) the content, orientation and composition of the ECM determined from MRI and cellular analysis. SA-3 will develop and validate a mesh-free multiscale (multi-cellular, compo- nent, and structural level) computational model, to establish mechanistic and causal links between subject- specific data from SA-1 and SA-2 to dynopenia with a focus on changes in lateral transmission of force. Such exhaustive characterization that targets all the major determinants of age-related force loss will enable us to (i) elucidate the role of ECM remodeling in dynopenia, (ii) identify surrogate imaging bio-markers for potential clinical applications, and (iii) assess the predictive power of the computational model to potentially inform the translational development of subject/ cohort-specific rehabilitative paradigms for a future RO1 grant.